Over the last 20 years, opioid prescriptions have increased substantially.1 Currently, opioids are among the most common medications prescribed by physicians in the US2 and Vicodin (hydrocodone/acetaminophen) -- with 100 million prescriptions in 2005 alone -- is the most commonly prescribed medication of any category.3 However, physical dependence (PD), addiction, and withdrawal complicate the use of prescription opioids. Among all Americans 12 years and older in 2006, 13.6 percent (more than 33 million) reported having used prescription opioids for nonmedical purposes at least once, more than 12 million in the prior year, and 5.2 million in the prior month.4 In 2001, the total cost of prescription opioid abuse in the US was estimated at $8.6 billion.5 For the purposes of this grant, we will use the term physical dependence (PD) to refer to that physiologic state induced by repeated or continuous drug use that manifests as withdrawal symptoms upon stopping use.6 This is not to be confused with the cluster of symptoms characterizing the DSM IV diagnosis of opioid dependence, which is additionally characterized by compulsion to take the drug, loss of control over the drug, and harm resulting from ongoing drug use. To avoid confusion between the terms physical dependence (PD) and opioid dependence as defined by the DSM IV, we will use the term addiction to refer to the biopsychosocial disease of drug use characterized by compulsive drug taking behaviors, preoccupation, and harm. The role of PD in the development of addiction is not established. There is currently no drug to prevent the progression of physical dependence and thus there has been no way to formally test the role it may or may not play in the progression from drug use to addiction. Furthermore, the uncomfortable and sometimes prolonged physical discomfort experienced by patients with PD in the setting of abstinence (opioid withdrawal), may reduce acceptance of abstinence-based therapies of opioid addiction. Thus, there is a need for effective strategies to treat the symptoms of opioid withdrawal (OW) created by abstinence in those with PD, and also to prevent progression of physical dependence associated with the use and abuse of prescription opioid medications. Recent evidence from pharmacogenetic haplotype-based computational mapping, animal studies, and several small pilot translational studies from this investigator's laboratory point to a significant role of the 5HT3 receptor in the expression of opioid withdrawal and physical dependence. The proposed studies will evaluate the use of 5HT3 receptor antagonists (5HT3-RAs) for new indications in the treatment of prescription opioid drug abuse. The overall HYPOTHESIS to be evaluated is that 5HT3-RAs can reduce opioid withdrawal symptoms in humans who have already developed physical dependence to opioids and prevent the progression of physical dependence when co-administered with opioid medications. We propose to test the ability of 5HT3-RAs to (1) reduce the expression of opioid withdrawal and (2) prevent the progression of physical dependence in chronic pain patients on chronic opioid therapy. To minimize the risks associated with the use of prescription opioids, we will enroll only patients who are already chronically exposed to opioids to treat chronic back pain. Furthermore, we have implemented a comprehensive 16-item Patient Safety Action Plan to maximize patient safety. We will exclude patients identified to be at elevated risk of addiction or of developing problematic opioid uses patterns. During the study, all participants will be carefully monitored by the PI, research nurse, and a board-certified physician with dual credentialing in addiction and pain medicine. At the end of the study, patients will be returned to their original prescription opioid regimen under daily monitoring from the Principal Investigator and an addiction expert. The Principal Investigator and addiction expert will be available unconditionally after the study in the unlikely event that any addiction issues arise. While there are inherent risks associated with the use of opioid pain medications, we are minimizing the additional risks of this study by restricting entry to only those people who have already adopted these risks through their ongoing clinical treatment. The additional level of screening and monitoring they will receive from the study will far exceed the level they would otherwise be exposed to in normal clinical practice, and this may reduce the associated opioid risks to below the levels experience by similar patients who do not participate in the study but are nonetheless exposed to chronic opioids.